The present invention relates to an agent for radio-actively imaging or otherwise evaluating the reticuloendothelial system (RES) of vertebrates, especially primates, particularly the bone marrow, the liver, and the lymph nodes. Such agents are sometimes referred to as radioactive RES agents. More particularly the invention relates to an RES agent comprising an extremely small sized .sup.99m Tc-labelled complex of a reducing metal and albumin (referred to hereinafter as a "minimicrocomplex"), particularly human serum albumin (HSA), to the unlabelled minimicrocomplex as such and in the form of a kit, to a method of making the same, and to methods of using the same for RES imaging and evaluation.
The reticuloendothelial system (RES) is a system comprised of most of the phagocytic cells in the body. These are cells which are able to dispose of foreign or other particles or cells by engulfing them, trapping them and/or metabolizing them. The RES includes the phagocytic cells which line the sinusoids of the liver (Kupffer cells), spleen, bone marrow, the lymphatic system, circulating macrophages, and phagocytic cells in certain other areas of the body. The organs of the RES have been effectively imaged with radiocolloids, which are taken up by the phagocytic cells. For example, RES agents injected into the blood stream are taken up and collected by the phagocytic cells in the RES, to give a latent radioactive image of the various components thereof, e.g., the liver, which can be converted into a visible image by appropriate instrumentation, e.g., by exposure of photographic film. Such images typically convey information about the size, shape, structure, location and/or condition of the various organs.
One area of particular importance in the field of pediatric health is bone marrow scintigraphy. Bone marrow imaging is indicated in both malignant and benign conditions. Many tumors, such as the neuroblastoma, metastasize to the bone marrow before there is involvement of the cortex of the bone. Similarly, leukemia and lymphoma may possibly be detected earlier by bone marrow imaging than by bone scanning. Eosinophilic granuloma primarily involves the bone marrow, and only later is the cortex of the bone affected. Infarction of bone is associated with decreased marrow activity, and thus bone marrow scintigraphy can also be useful in distinguishing infarction from the infection of bone.
Certain RES agents can be used to image the lymphatic system or portions thereof, more specifically either by direct injection into the lymphatic channels by interstitial injection (e.g., intramuscular, peri-prostatic), or by intraperitoneal injection, whereby the interstitial fluid and lymph carry the RES agent through the lymphatic system to various lymph nodes, where barring saturation and/or blockage of those lymph nodes in certain, typically metastatic, disease states they are requested by reticuloendothelial components of the nodes. By use of such RES agents, the lymph nodes in which such agents are collected can be imaged in a manner similar to the imaging of other organs. Radioscintigraphic imaging of the lymph nodes or other components of the lymphatic system is termed "lymphoscintography."
At one time the most common commercial RES imaging agent was a radiocolloid (particle size of 0.001-0.05 micrometers (.mu.m)) of gold-198 (.sup.198 Au), stabilized with gelatin. However, these gold-198 imaging agents did not have the optimum physical characteristics for imaging, and gold-198 had an undesirably long half life, thus subjecting the RES and surrounding tissue to undesirably high dosages of radiation. Accordingly, with the advent of RES imaging agents utilizing the shorter half-life technetium-99m (.sup.99m Tc), the use of the gold-198 agents has been almost completely supplanted.
One of the technetium-99m based RES agents is .sup.99m Tc-labelled sulfur colloid-stabilized with gelatin, most of which has a particle size of &lt;0.1-1.0 .mu.m. This is presently still the most widely used radioactive RES imaging agent, despite a number of serious disadvantages, including: (a) requiring a relatively large number of components; (b) requiring boiling and neutralization steps for labelling by the user at the use situs, making the preparation of the agent for use both time consuming and cumbersome; and (c) not being biodegradable, and thus not being easily and quickly eliminated from the body. Following intravenous injection most of the sulfur colloid RES agents on the market do give sharp clear simultaneous images of the liver and spleen, although they are difficult to prepare. They are also used for imaging bone marrow. Although .sup.99m Tc-labelled sulfur colloid is also used for imaging lymph nodes, the safety and efficacy of the available preparations are generally limited. When injected interstitially, most of the particles remain at the site of the interstitial injection, inflicting an undesirable radiation burden on that non-target tissue. Furthermore, it has been reported that when such particles are carried to lymph nodes, they seldom are carried beyond the first lymph node they encounter, even when that node is not otherwise obstructed. This makes it difficult to image a series or chain of lymph nodes, or to evaluate the extent to which lymph nodes in various locations have been obstructed as a result of a disease condition.
A .sup.99m Tc-labelled stannous hydroxide colloid has also been marketed as an RES agent but it is a disadvantage in that it is difficult to prevent growth of the colloidal particles after labelling without the subsequent addition of stabilizers by the user at the use situs, which make them unsatisfactory for RES imaging; i.e., they are not stable.
Another RES agent which has been marketed in small quantities is a .sup.99m Tc-labelled stannous phytate complex which, it is believed, is converted to an insoluble colloid by calcium in the bloodstream or lymph or interstitial fluid, from which it is then removed by the RES. However, with this agent, deficiencies have been found with respect to both retention at the injection site and uptake by the lymph nodes.
A .sup.99m Tc-labelled antimony sulfide colloid has been reported as being commercially available certain countries, and is presently undergoing testing for use in the United States and Canada. While this material apparently does provide improved lymphoscintigraphic results as compared with the .sup.99m Tc-labelled sulfur colloid and stannous phytate agents, it still suffers from the disadvantages that it is time consuming and difficult to prepare by the user, since preparation requires mixing with a stabilizer, boiling for a substantial time, cooling, buffering dilution to administration concentration, and pH testing, before use. Moreover, many of these steps must be taken with the radioactive material being outside of its shielded enclosure. Further, the antimony sulfide, like the sulfur colloid agent, is not biodegradable.